WO2001097848A2 - Agents pharmaceutiques antagonistes du recepteur de vitronectine, a utiliser en polytherapie - Google Patents

Agents pharmaceutiques antagonistes du recepteur de vitronectine, a utiliser en polytherapie Download PDF

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Publication number
WO2001097848A2
WO2001097848A2 PCT/US2001/019793 US0119793W WO0197848A2 WO 2001097848 A2 WO2001097848 A2 WO 2001097848A2 US 0119793 W US0119793 W US 0119793W WO 0197848 A2 WO0197848 A2 WO 0197848A2
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Prior art keywords
alkyl
substituted
aryl
methyl
cycloalkyl
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PCT/US2001/019793
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English (en)
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WO2001097848A3 (fr
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Thomas D. Harris
John A. Barrett
Alan P. Carpenter, Jr.
Milind Rajopadhye
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Bristol-Myers Squibb Pharma Company
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Priority to AU7296501A priority Critical patent/AU7296501A/xx
Priority to CA2412854A priority patent/CA2412854C/fr
Priority to NZ522925A priority patent/NZ522925A/en
Priority to IL15294101A priority patent/IL152941A0/xx
Priority to EP01952180A priority patent/EP1307226B1/fr
Priority to JP2002503332A priority patent/JP2004521066A/ja
Priority to BRPI0111880-3A priority patent/BR0111880A/pt
Priority to AU2001272965A priority patent/AU2001272965C1/en
Priority to DE60136632T priority patent/DE60136632D1/de
Priority to MXPA02012750A priority patent/MXPA02012750A/es
Publication of WO2001097848A2 publication Critical patent/WO2001097848A2/fr
Publication of WO2001097848A3 publication Critical patent/WO2001097848A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention provides novel pharmaceuticals useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient.
  • the invention is also directed to novel pharmaceutical compositions and combination therapy comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and at least one agent selected from the group consisting of an anti-cancer agent and a radiosensitizer agent.
  • the invention is directed to novel pharmaceutical compositions and combination therapy comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and a photosensitizing agent.
  • the pharmaceuticals are comprised of a targeting moiety that binds to the vitronectin receptor that is expressed in tumor vasculature, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety.
  • the therapeutically effective radioisotope emits a gamma ray or alpha particle sufficient to be cytotoxic.
  • the imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.
  • Cancer is a major public health concern in the United States and around the world. It is estimated that over 1 million new cases of invasive cancer will be diagnosed in the United States in 1998. The most prevalent forms of the disease are solid tumors of the lung, breast, prostate, colon and rectum. Cancer is typically diagnosed by a combination of in vitro tests and imaging procedures.
  • the imaging procedures include X-ray computed tomography, magnetic resonance imaging, ultrasound imaging and radionuclide scintigraphy.
  • a contrast agent is administered to the patient to enhance the image obtained by X-ray CT, MRI and ultrasound, and the administration of a radiopharmaceutical that localizes in tumors is required for radionuclide scintigraphy.
  • Treatment of cancer typically involves the use of external beam radiation therapy and chemotherapy, either alone or in combination, depending on the type and extent of the disease.
  • a number of chemotherapeutic agents are available, but generally they all suffer from a lack of specificity for tumors versus normal tissues, resulting in considerable side-effects.
  • the effectiveness of these treatment modalities is also limited, as evidenced by the high mortality rates for a number of cancer types, especially the more prevalent solid tumor diseases. More effective and specific treatment means continue to be needed.
  • metallopharmaceutical that localizes specifically in the tumor by binding to a receptor expressed only in tumors or expressed to a significantly greater extent in tumors than in other tissue.
  • the location of the metallopharmaceutical could then be detected externally either by its imageable emission in the case of certain radiopharmaceuticals or by its effect on the relaxation rate of water in the immediate vicinity in the case of magnetic resonance imaging contrast agents.
  • This tumor specific metallopharmaceutical approach can also be used for the treatment of cancer when the metallopharmaceutical is comprised of a particle emitting radioisotope.
  • the radioactive decay of the isotope at the site of the tumor results in sufficient ionizing radiation to be toxic to the tumor cells.
  • the specificity of this approach for tumors minimizes the amount of normal tissue that is exposed to the cytotoxic agent and thus may provide more effective treatment with fewer side-effects.
  • radionuclide labeled monoclonal antibodies, antibody fragments and other proteins or polypeptides that bind to tumor cell surface receptors have centered on the use of radionuclide labeled monoclonal antibodies, antibody fragments and other proteins or polypeptides that bind to tumor cell surface receptors.
  • the specificity of these radiopharmaceuticals is frequently very high, but they suffer from several disadvantages.
  • due to their molecular weight do not extravasate readily at the site of the tumor and then only slowly diffuse through the extravascular space to the tumor cell surface. This results in a very limited amount of the radiopharmaceutical reaching the receptors and thus very low signal intensity in imaging and insufficient cytotoxic effect for treatment.
  • Angiogenesis is the process by which new blood vessels are formed from pre-existing capillaries or post capillary venules ; it is an important component of a variety of physiological processes including ovulation, embryonic development, wound repair, and collateral vascular generation in the myocardium. It is also central to a number of pathological conditions such as tumor growth and metastasis, diabetic retinopathy, and macular degeneration.
  • the process begins with the activation of existing vascular endothelial cells in response to a variety of cytokines and growth factors . Tumor released cytokines or angiogenic factors stimulate vascular endothelial cells by interacting with specific cell surface receptors for the factors.
  • the activated endothelial cells secrete enzymes that degrade the basement membrane of the vessels.
  • the endothelial cells then proliferate and invade into the tumor tissue.
  • the endothelial cells differentiate to form lumens, making new vessel offshoots of pre-existing vessels.
  • the new blood vessels then provide nutrients to the tumor permitting further growth and a route for metastasis.
  • endothelial cell proliferation is a very slow process, but it increases for a short period of time during embryogenesis, ovulation and wound healing. This temporary increase in cell turnover is governed by a combination of a number of growth stimulatory factors and growth suppressing factors. In pathological angiogenesis, this normal balance is disrupted resulting in continued increased endothelial cell proliferation.
  • proangiogenic factors include basic fibroblast growth factor (bFGF) , angiogenin, TGF- alpha, TGF-beta, and vascular endothelium growth factor (VEGF) .
  • bFGF basic fibroblast growth factor
  • angiogenin TGF- alpha
  • TGF-beta TGF-beta
  • VEGF vascular endothelium growth factor
  • interferon-alpha, interferon-beta and thrombospondin are examples of angiogenesis suppressors.
  • Integrins are a diverse family of heterodimeric cell surface receptors by which endothelial cells attach to the extracellular matrix, each other and other cells.
  • the integrin ⁇ v ⁇ 3 is a receptor for a wide variety for a wide variety of extracellular matrix proteins with an exposed tripeptide Arg-Gly-Asp moiety and mediates cellular adhesion to its ligand: vitronectin, fibronectin, and fibrinogen, among others.
  • the integrin ⁇ v ⁇ 3 is minimally expressed on normal blood vessels, but is significantly upregulated on vascular cells within a variety of human tumors .
  • the role of the v ⁇ 3 receptors is to mediate the interaction of the endothelial cells and the extracellular matrix and facilitate the migration of the cells in the direction of the angiogenic signal, the tumor cell population.
  • Angiogenesis induced by bFGF or TNF-alpha depend on the agency of the integrin 0t v ⁇ 3
  • angiogenesis induced by VEGF depends on the integrin v ⁇ 3 (Cheresh et. al . , Science, 1955, 270, 1500-2).
  • Induction of expression of the integrins ⁇ and ⁇ on the endothelial cell surface is another important mechanism by which VEGF promotes angiogenesis (Senger, et . al . , Proc. Natl. Acad, Sci USA, 1997, 84, 13612-7) .
  • Angiogenic factors interact with endothelial cell surface receptors such as the receptor tyrosine kinases EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, tie, neuropilin-1, endoglin, endosialin, and Axl .
  • the receptors Flk-1/KDR, neuropilin-1, and Flt-1 recognize VEGF and these interactions play key roles in VEGF- induced angiogenesis.
  • the Tie subfamily of receptor tyrosine kinases are also expressed prominently during blood vessel formation.
  • angiostatin is a 38 kDa fragment of plasminogen that has been shown in animal models to be a potent inhibitor of endothelial cell proliferation.
  • Endostatin is a 20 kDa C-terminal fragment of collagen XVIII that has also been shown to be a potent inhibitor.
  • Endostatin Systemic therapy with endostatin has been shown to result in strong anti-tumor activity in animal models.
  • human clinical trials of these two chemotherapeutic agents of biological origin have been hampered by lack of availability.
  • Another approach to anti-angiogenic therapy is to use targeting moieties that interact with endothelial cell surface receptors expressed in the angiogenic vasculature to which are attached chemotherapeutic agents.
  • Burrows and Thorpe Proc. Nat. Acad. Sci, USA, 1993, 90, 8996-9000
  • the antibody was raised against an endothelial cell class II antigen of the major histocompatibility complex and was then conjugated with the cytotoxic agent, deglycosylated ricin A chain. The same group (Clin. Can.
  • the receptor targets for the radiopharmaceutical compounds, used in this method of treatment are expressed on the luminal side of tumor vessels, there is no requirement that these compounds traverse the capillary bed and bind to the tumor itself.
  • Photodynamic therapy has also been used in the treatment of cancer. Photodynamic therapy involves the administration of a photosensitive agent and subsequent irradiation with light to excite the photosensitizer, thus producing a cytotoxic effect. Spears, U.S. Pat. No. 4,512,762, and U.S. Pat. No. 4,566,636, Kelly, et al . United States Patent 6,235,767.
  • the photosensitizers used are capable of localizing in malignant cells, either by natural tendency or because they have been intentionally targeted to a specific type of tissue, or both. When irradiated, they may be capable of fluorescing and, thus, may also be useful in diagnostic methods related to detecting target tissue.
  • the photosensitizer has the capacity, when irradiated with light at a wavelength which the compound absorbs, of causing a cytotoxic effect against whatever cells or other tissue in which the photosensitizer has localized.
  • a photosensitizer agent having a characteristic light absorption waveband is first administered to the patient, typically either orally or by injection.
  • Abnormal tissue in the body is known to selectively absorb certain photosensitizer agents to a much greater extent than normal tissue. More effective selectivity can be achieved using a photoreactive agent that is bound to an antibody, which links with antigens on targeted cells . The cancerous or abnormal tissue that has absorbed or linked with the photosensitizer dye is then destroyed by administering light of an appropriate wavelength or waveband corresponding to the absorption wavelength or waveband of the photosensitizer agent.
  • Photosensitizing agents such as Photofrin, a haematoporphyrin derivative, are known.
  • Photosensitizers therapy and detection of malignant tumours. Photochem. Photobiol . , 45, 879-889, and Boyle R. W. and D. David (1996) Structure and biodistribution relationships of photodynamic sensitizers. Photochem. Photobiol. 64, 469-485)
  • Rodgers,et al . United States Patent No.
  • 6,225,333 discloses treating cancers with a variety of photosensitizing agents for example naphthalocyanine photosensitizing agents; tetrapyrrole-based photosensitizers; including porphyins; chlorins;, phthalocyanines; napthalocyanines ; coumarins and psoralens. Furthermore, Mazur, et al . , United States Patent No.
  • 6,229,0408 discloses a method for treatment of solid tumors by photodynamic therapy comprising administering a photosensitizer selected from the group consisting of: 1, 3 , 4, 6-tetrahydroxyhelianthrone; 1, 3 , 4, 6-tetramethoxyhelianthrone; 10 , 13 -dimethyl- 1,3,4, 6-tetrahydroxyhelianthrone; 10, 13- di (methoxycarbonyl) -1,3,4, 6-tetramethoxyhelianthrone; 1, 6-di-N-butylamino-3 , 4-dimethoxy-helianthrone; 1, 6-di- N-butylamino-3 , 4-dimethoxy-10 , 13-dimethyl-helia throne; 1, 6-di- (N-hydroxyethylamino) -3 , 4-dimethoxy-helianthrone; 2, 5-dibromo-l, 3 , 4, 6-tetrahydroxyhelianthrone; and 2,5- dibro
  • a light-emitting balloon catheter may be used or alternatively, a form of "liquid light” may be injected into the vascular tree such that the "liquid light”, perfuses the vasculature at the target site. Spears, U.S. Pat. No. 4,512,762. Alternatively,
  • the targeted tissues are visually located by imaging the treatment site through a fiber optic system so that light from a laser source can be accurately directed through the optical fiber to destroy the abnormal tissue. Even when the internal treatment site is accessible through natural body orifices, an endoscope is usually required to visualize the targeted tissue and accurately direct the light therapy administered to the treatment site.
  • Chen, United States Patent No. 6,210,425 discloses an apparatus and a method to identify an internal treatment site within a patient's body for administration of light therapy and treatment of the site.
  • a photosensitizer agent as part of photodynamic therapy
  • an angiogenesis-targeted therapeutic radiopharmaceutical and an anti-cancer agent or a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, which target the luminal side of the neovasculature of tumors, to provide a surprising, and enhanced degree of tumor suppression relative to each treatment modality alone without significant additive toxicity.
  • RA rheumatoid arthritis
  • the main applications that are under investigation in a number of laboratories are for improving cardiac blood flow and in improving peripheral vessal blood flow in the limbs.
  • Henry, T. et. al . J. Amer.
  • cardiovascular diseases need to be improved, including restenosis, atherosclerosis, myocardial reperfusion injury, and myocardial ischemia, stunning or infarction. It has recently been determined that in all of these disease conditions, the integrin receptor v ⁇ 3 plays an important role.
  • neointimal hyperplasia and ultimate reocclusion is caused by aggressively proliferating vascular smooth muscle cells that express ⁇ v ⁇ 3.
  • Atherosclerosis proceeds from an intial endothelial damage that results in the recruitment and subintimal migration of monocytes at the site of the injury. Growth factors are released which induce medial smooth muscle cells to proliferate and migrate to the inti al layer. The migrating smooth muscle cells express ⁇ v ⁇ 3.
  • neutrophil transmigration is integrin dependent and the integrins moderate initial infiltration into the viable border zone.
  • the induction of 5 ⁇ l, 4 ⁇ l and ⁇ v ⁇ 5 in infiltrating neutrophils occurs within 3 to 5 hours after reperfusion as neutrophils move from the border zone to the area of necrosis. (Circulation, 1999, 100, 1-275) ⁇
  • Acute or chronic occlusion of a coronary artery is known to result in angiogenesis in the heart as native collateral vessels are recruited to attempt to relieve the ischemia.
  • a gradual occlusion usually results in areas of infarction as the resulting angiogenesis is not sufficient to prevent damage.
  • Cardiac angiogenesis has been associated with increased expression of the growth factors VEGF and FGF and the upregulation of the growth factor receptors flt-1 and flk-1/KDR. (Drugs, 1999, 58, 391-396).
  • the vitronectin receptor binding compounds target the radioisotope to the tumor neovasculature.
  • the beta or alpha-particle emitting radioisotope emits a cytotoxic amount of ionizing radiation which results in cell death. The penetrating ability of radiation obviates the requirement that the cytotoxic agent diffuse or be transported into the cell to be cytotoxic.
  • These pharmaceuticals comprise a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a radioisotope that emits cytotoxic radiation (i.e., beta particles, alpha particles and Auger or Coster-Kronig electrons) .
  • cytotoxic radiation i.e., beta particles, alpha particles and Auger or Coster-Kronig electrons
  • the radiopharmaceuticals of the present invention that emit cytotoxic radiation could be used to destroy the new angiogenic vasculature that results and thus treat the disease.
  • kits and therapeutic radiopharmacutical compositions for use in combination therapy comprising a radiopharmacutical of the invention and at least one agents selected from the group consisting of an anti- cancer agent and a radiosensitizer agent.
  • kits and therapeutic radiopharmacutical compositions for use in combination therapy comprising a radiopharmacutical of the invention and a photosensitising agent.
  • It is another object of the present invention to provide a method of treating cancer comprising administering to a patient in need of such treatment a therapeutic radiopharmaceutical composition of the invention in combination with photodynamic therapy.
  • These compounds are comprised of a non-peptide quinolone containing targeting moiety that binds to a receptor that is upregulated during angiogenesis or during cardiovascular diseases, Q, an optional linking group, L n , and a metal chelator or bonding moiety, C h -
  • the compounds may have one or more protecting groups attached to the metal chelator or bonding moiety. The protecting groups provide improved stability to the reagents for long-term storage and are removed either immediately prior to or concurrent with the synthesis of the radiopharmaceuticals.
  • the compounds of the present invention are comprised of a peptide or peptidomimetic targeting moiety that binds to a receptor that is upregulated during angiogenesis or during cardiovascular diseases, Q, an optional linking group, L n , and a surfactant, S f .
  • the pharmaceuticals of the present invention may be used for diagnostic and/or therapeutic purposes.
  • Diagnostic radiopharmaceuticals of the present invention are pharmaceuticals comprised of a diagnostically useful radionuclide (i.e., a radioactive metal ion that has imageable gamma ray or positron emissions) .
  • Therapeutic radiopharmaceuticals of the present invention are pharmaceuticals comprised of a therapeutically useful radionuclide, a radioactive metal ion that emits ionizing radiation such as beta particles, alpha particles and Auger or Coster-Kronig electrons .
  • the pharmaceuticals comprising a gamma ray or positron emitting radioactive metal ion are useful for imaging tumors and by gamma scintigraphy or positron emission tomography.
  • the pharmaceuticals comprising a gamma ray or positron emitting radioactive metal ion are also useful for imaging therapeutic angiogenesis, natural angiogenic processes in response to acute or chronic coronary vessel occlusion, restenosis post- angioplasty, atherosclerosis and plaque formation, and reperfusion injury by gamma scintigraphy or positron emission tomography.
  • the pharmaceuticals comprising a particle emitting radioactive metal ion are useful for treating cancer by delivering a cytotoxic dose of radiation to the tumors.
  • the pharmaceuticals comprising a particle emitting radioactive metal ion are also useful for treating rheumatoid arthritis by destroying the formation of angiogenic vasculature.
  • the pharmaceuticals comprising a paramagnetic metal ion are useful as magnetic resonance imaging contrast agents.
  • the pharmaceuticals comprising one or more X-ray absorbing or "heavy" atoms of atomic number 20 or greater are useful as X-ray contrast agents.
  • the pharmaceuticals comprising a microbubble of a biocompatible gas, a liquid carrier, and a surfactant microsphere, are useful as ultrasound contrast agents.
  • the present invention provides a kit for treating cancer, comprising a compound of the formula (I) and at least one agent selected from the group consisting of an anti-cancer agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the compound of the formula (I) is:
  • R ⁇ e is selected from:
  • a e is -CH2- or -N(R 10e )-;
  • a le and B e are independently -CH2- or -N(R 10e )-;
  • D e is -N(R 10e )- or -S-;
  • J e is -C(R 2e )- or -N-;
  • K e , L e and M e are independently -C(R 2e )- or -C(R 3e )-;
  • R e and R 3e are independently selected from:
  • R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2 ;
  • R2ae j_ s selected from:
  • R ⁇ e is selected from:
  • U e is selected from:
  • Cio alkylcarbonyl, -N(R lle )R 12e , cyano, halo, CF3, CHO, C02R 18be , C( 0)R 18be , C0NR 17e R 18be ,
  • NR 10e SO2R 21e S(0) p R lle , S ⁇ 2NR 10e R lle , aryl substituted with 0-3 groups selected from halogen, C ⁇ C6 alkoxy, Ci-C ⁇ alkyl, CF3 ,
  • plOe j_ s selected from:
  • R ⁇ e is selected from:
  • R 4e is selected from:
  • Rl ⁇ e and R ⁇ e are both substituents on the same nitrogen atom (as in - RlO e RU- e ) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1,2,3,4- tetrahydro-1-quinolinyl, 1, 2 , 3 , 4-tetrahydro-2- isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1- pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl ; said heterocycle being substituted with 0-3 groups selected from: C1-C6 alkyl, aryl, heteroaryl, aryl(C ⁇ -C4 alkyl)-, (C1-C6 alkyl ) carbonyl , (C3-C7 cycloalkyl) carbonyl, (C1-C6 alkoxy)
  • R 12e ig selected from: H, C1-C6 alkyl, triphenylmethyl , methoxymethyl, methoxyphenyldiphenylmethyl , trimethylsilylethoxymethyl, (Ci-C ⁇ alkyl) carbonyl, (Ci-C ⁇ alkoxy) carbonyl, (C1-C6 alkyl ) aminocarbonyl , C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, heteroaryl (C ⁇ -C6 alkyl ) carbonyl , heteroarylcarbonyl, aryl(C ⁇ -C6 alkyl)-, (Ci-C ⁇ alkyl ) carbonyl , arylcarbonyl, Ci-C ⁇ alkylsulfonyl, arylsulfonyl, aryl (C1-C6 alkyl) sulfon
  • R 16e j_ s selected from:
  • R 17e is selected from:
  • C1-C6 alkyl C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, aryl (C1-C6 alkyl)-, and heteroaryl (C1-C6 alkyl);
  • pl ⁇ ae j_ s selected from:
  • C ⁇ -C8 alkyl optionally substituted with a bond to Ln
  • C3-C11 cycloalkyl optionally substituted with a bond to L n
  • heteroaryl Ci-C ⁇ alkyl)- optionally substituted with a bond to L n
  • biaryl optionally substituted with a bond to L n/ heteroaryl optionally substituted with a bond to L n» phenyl substituted with 3-4 R ⁇ e anc j optionally substituted with a bond to L n
  • naphthyl substituted with 0-4 R ⁇ e anc j optionally substituted with a bond to L
  • R 18be is H or R 18ae.
  • R 19e £ s selected from:
  • Y r (5-(C ⁇ -C5 alkyl) -1, 3-dioxa-cyclopenten-2-one- yl)methyloxy, (5-aryl-l, 3-dioxa-cyclopenten-2-one-yl)methyloxy, and
  • R 21e is selected from:
  • C1-C8 alkyl C2-C6 alkenyl, C3-C11 cycloalkyl, (C3- Cl l cycloalkyl)methyl, aryl, aryl(C ⁇ -C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R 7e ;
  • R 22e i s selected from:
  • Y e is selected from:
  • n e is 0-4;
  • p e is 0-2;
  • r e is 0-2;
  • n e and m e are chosen such that the number of atoms connecting R ⁇ e and Y e is in the range of 8-14;
  • d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • d' is 1-100
  • L n is a linking group having the formula:
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-3 R!°, C3-10 cycloalkyl substituted with 0-3 R 11 ⁇ , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 1 ⁇ ;
  • R 11 is independently selected at each occurrence from the group: H, -OPO3H2 , , -OSO3H C1-5 alkyl substituted with 0-1 R 12 , aryl substituted with 0-1
  • R 12 a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 12 , C3-10 cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 1 , C ⁇ _5 alkyl substituted with carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1
  • R 12 amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 1 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, alkyl substituted with 3 , 6-O-disulfo-B-D- galactopyranosyl, bis (phosphonomethyl) glycine, and a bond to Ch;
  • R 12 is a bond to Ch
  • s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and
  • Ch is a metal bonding unit having a formula selected from the group:
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 5 , A 7 , and A 8 are independently selected at each occurrence from the group : NR , NR 13 R 14 , S, SH, S(Pg), 0, OH, PR 13 , PR 13 R 14 , P(0)R 15 R 16 , and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Cl-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C3-10 cycloalkyl substituted with 0-3
  • heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and
  • R 13 and R 14 are each independently selected from the group: a bond to L n , hydrogen, C1.-C10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , Ci-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-Ci-io alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, C6-10 aryl-Ci-io alkyl substituted with 0-3 R 17 , Ci-io alkyl-C ⁇ -io aryl- substituted with 0-3 R 7 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 , and an electron, provided that when one of R 3 or R 14 is an electron, then the other is also an electron;
  • R 8 , R 1 a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, Ci-C ⁇ alkyl, phenyl, benzyl, Ci-C ⁇ alkoxy, halide, nitro, cyano, and trifiuoromethyl;
  • Pg is a thiol protecting group
  • R 2 0 and R 21 are independently selected from the group:
  • R 23 C2-C10 1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 23 , and unsaturated C3-10 carbocycle substituted with 0-3 R 23 ;
  • R ⁇ and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group:
  • R 24 Cl-Cio alkyl substituted with 0-3 R 24 , c 2-Ci ⁇ alkenyl substituted with 0-3 R 24 , C2-C10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3
  • R 24 and C3-10 carbocycle substituted with 0-3 R 24 ;
  • R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0;
  • a and b indicate the positions of optional double bonds and n is 0 or 1;
  • R 25 , R 5a , and R ⁇ are each independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a kit according to Embodiment [1] wherein said kit comprises a plurality of separate containers, wherein at least one of said containers contains one or more agents selected from the group consisting of an anti-cancer agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and another of said containers contains a compound of formula (I) : (Q)d-Ln-Ch or ( Q) d ⁇ Ln ⁇ ( Ch ) d'
  • R le is selected from:
  • a e is -CH2- or -N(R 10e )-;
  • a le and B e are independently -CEt ⁇ - or -N(R 10e )-;
  • D e is -N(R 10e )- or -S-;
  • E e_ F e i g _ C ( R 2e ) C ( R 3e)_ or _ c (R 2e) 2C (R 3e) 2 _ .
  • J e is -C (R 2 e ) - or -N- ;
  • K e , L e and M e are independently -C(R 2e )- or -C(R 3e )-;
  • R 2e and R 3e are independently selected from:
  • R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
  • R 7e is selected from:
  • U e is selected from: -(CH 2 ) n e -, -(CH2 ) n e O ( CH 2 )m e -, -
  • G e is N or CR 19e ;
  • R ⁇ e is selected from: H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C ⁇
  • NR 10e SO2R 21e S(0) p R lle , S ⁇ 2NR 10e R lle , aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3 ,
  • R 1 ⁇ is selected from:
  • R l e is selected from:
  • R 4e is selected from:
  • R 12e ig selected from:
  • C1-C6 alkyl triphenylmethyl , methoxymethyl , methoxyphenyldiphenylmethyl , trimethylsilylethoxymethyl, (C1-C6 alkyl ) carbonyl , (C1-C6 alkoxy) carbonyl, (Ci-C ⁇ alkyl) aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, heteroaryl (Ci-C ⁇ alkyl) carbonyl, heteroarylcarbonyl, aryl (Ci-C ⁇ alkyl)-, (Ci-Cg alkyl) carbonyl, arylcarbonyl, C1-C alkylsulfonyl, arylsulfonyl, aryl (C1-C6 alkyl ) sulfonyl , heteroarylsulfonyl
  • R 17e is selected from:
  • C1-C6 alkyl C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, aryl(C ⁇ -C6 alkyl)-, and heteroaryl (C1-C6 alkyl);
  • Cl ⁇ C8 alkyl optionally substituted with a bond to Ln, C3-C11 cycloalkyl optionally substituted with a bond to L n , aryl (C1-C6 alkyl) - optionally substituted with a bond to L n , heteroaryl (Ci-C ⁇ alkyl)- optionally substituted with a bond to L n , (C1-C6 alkyl) heteroaryl optionally substituted with a bond to L n , biaryl (C1-C6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted
  • R 18be is H or R 18ae.
  • R 19e ig selected from:
  • R 20e i s selected from: hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, aryloxy, aryl(C ⁇ C4 alkyl) oxy, C2-C10 alkylcarbonyloxy (C1-C2 alkyl) oxy-, c 2 ⁇ ⁇ o alkoxycarbonyloxy (C1-C2 alkyl) oxy-, c 2 ⁇ Cl ⁇ alkoxycarbonyl (C1-C2 alkyl) oxy-,
  • R 21e ig selected from:
  • C1-C8 alkyl C2-C6 alkenyl, C3-C11 cycloalkyl, (C3- Cll cycloalkyl) methyl, aryl, aryl (C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R 7e ;
  • Y e is selected from:
  • n e is 0-4 ;
  • p e is 0-2 ;
  • r e is 0-2 ;
  • n e and m e are chosen such that the number of atoms connecting R le and Y e is in the range of 8-14;
  • d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • d' is 1-100
  • L n is a linking group having the formula:
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-3 R 10 , C3-10 cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 0 ;
  • R 11 is independently selected at each occurrence from the group: H, -OPO3H2,, -OSO3H C ⁇ _5 alkyl substituted with 0-1 R 12 , aryl substituted with 0-1
  • R 12 a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 12 ,
  • R 12 is a bond to Ch
  • Ch is a metal bonding unit having a formula selected from the group :
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 1 R 14 , S, SH, S(Pg), 0, OH, PR 13 , PR 13 R 14 , P(0)R 15 R 16 , and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C3-10 cycloalkyl substituted with 0-3
  • heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and
  • Ci-io alkyl-C6-10 aryl- substituted with 0-3 R 17 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 ;
  • R 13 and R 14 are each independently selected from the group: a bond to L n , hydrogen, Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , Ci-io cycloalkyl substituted with 0-3 R 17 , heterocyclo-Ci-io alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, Cg-10 aryl-Ci-io alkyl substituted with 0-3 R 17 , C ⁇ _ ⁇ o alkyl-C6-10 aryl- substituted with 0-3 R 17 , a
  • R 15 and R 1 ⁇ are each independently selected from the group: a bond to L n , -OH, Ci-Cio alkyl substituted with 0-3 R 17 , Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C3-10 cycloalkyl substituted with 0-3 R 17 , heterocycl ⁇ Ci-io alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, C6-10 aryl-Ci-10 alkyl substituted with 0-3 R 17 , Ci-io alkyl-C6-10 aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 ;
  • R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, Ci-C ⁇ alkyl, phenyl, benzyl, C1-C6 alkoxy, halide, nitro, cyano, and trifiuoromethyl;
  • Pg is a thiol protecting group
  • R ⁇ and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group:
  • R 24 C1-C10 alkyl substituted with 0-3 R 24 , C2-C10 alkenyl substituted with 0-3 R 24 , C2-C10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 24 , and C3-10 carbocycle substituted with 0-3 R 24 ;
  • R 25 , R 25a , and R 2 ⁇ are each independently selected at each occurrence from the group: hydrogen and Ci-C ⁇ alkyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a kit according to Embodiment [1] , wherein the anti-cancer agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethi ide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etre
  • the present invention provides a kit according to Embodiment [1] , wherein the anti-cancer agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, a sacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etret
  • the present invention provides a kit according to Embodiment [1] wherein the anti-cancer agent is selected from the group consisting of oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, and formestane.
  • the present invention provides a kit according to Embodiment [1] wherein the anti-cancer agent is selected from the group consisting of interferon-alpha, interferon-2 alpha, interferon- beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor.
  • the present invention provides a kit according to Embodiment [1] , wherein radiosensitizer agent is selected from the group consiting of 2- (3-nitro-l, 2 , 4-triazol-l-yl) -N- (2- methoxyethyl ) acetamide, N- (3-nitro-4-quinolinyl) -4- morpholinecarboxamidine, 3-amino-l, 2 , 4-benzotriazine- 1, 4-dioxide, N- (2-hydroxyethyl) -2-nitroimidazole-l- acetamide, 1- (2-nitroimidazol-l-yl) -3- (1-piperidinyl) - 2-propanol, and 1- (2-nitro-l-imidazolyl) -3- (1- aziridino) -2-propanol .
  • the present invention provides a kit according to Embodiment [1] , wherein Q is selected from the group consiting of 2- (3-nitro
  • R le is selected from:
  • R 2e and R e are independently selected from:
  • R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and N0 ;
  • R 2ae is selected from: H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl), aryl, aryl(C ⁇ -C4 alkyl)-, (C2-C7 alkyl) carbonyl, arylcarbonyl , (C2-C10 alkoxy) carbonyl, C3-C7 cycloalkoxycarbonyl, C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl (C1-C 0 alkoxy) carbonyl ,
  • R 7e is selected from:
  • U e is selected from:
  • R 9e is selected from:
  • R ⁇ e is selected from:
  • Ci-Cio alkyl H, Ci-Cio alkyl, hydroxy, Ci-Cio alkoxy, nitro, C ⁇
  • Cio alkylcarbonyl, -N(R lle ) R 12e , cyano, halo, CF3, CHO, C02R 18be , C( 0)R 18be , CONR 17e R 18be ,
  • NR 10e SO2R 21e S(O) p e R lle , S ⁇ 2NR 10e R lle , aryl substituted with 0-3 groups selected from halogen, C ⁇ C6 alkoxy, Ci-Cs alkyl, CF3 ,
  • Rile is selected from:
  • Ci-Cs alkyl C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl) methyl, C1-C6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl (Ci- C4 alkyl)-, aryl(C ⁇ -C4 alkyl), adamantylmethyl, and
  • R 4e is selected from: H, Ci-C alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl (C ⁇ -C ⁇ alkyl)-, aryl, heteroaryl, aryl(C- j _-Cg alkyl)-, and heteroaryl (C ⁇ -Cg alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl,
  • R 12e is selected from:
  • C1-C6 alkyl triphenylmethyl , methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (Ci-C ⁇ alkyl) carbonyl, (Ci-C ⁇ alkoxy) carbonyl, (Ci-Cg alkyl) aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, heteroaryl (Ci-C ⁇ alkyl) carbonyl, heteroarylcarbonyl, aryl(C ⁇ -C6 alkyl)-, (Ci-C ⁇ alkyl ) carbonyl , arylcarbonyl, Ci-C ⁇ alkylsulfonyl, arylsulfonyl, aryl (Ci-C ⁇ alkyl) sulfonyl, heteroarylsulfonyl, heteroaryls
  • Ri6e is selected from:
  • R 17e is selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, aryl (C1-C6 alkyl)-, and heteroaryl (C1-C6 alkyl);
  • R 18ae ig selected from: C1-C8 alkyl optionally substituted with a bond to L n C3-C11 cycloalkyl optionally substituted with a bond to L n , aryl(C ⁇ -C6 alkyl) - optionally substituted with a bond to L n , heteroaryl (Ci-Cg alkyl)- optionally substituted with a bond to L n , (Ci-C ⁇ alkyl) heteroaryl optionally substituted with a bond to L n , biaryl (C1-C6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said ary
  • R 1 e is selected from:
  • R 20e is selected from: hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, aryloxy, aryl(C ⁇ -C4 alkyl) oxy, C2-C10 alkylcarbonyloxy (C1-C2 alkyl) oxy-, 2- 10 alkoxycarbonyloxy (C1-C2 alkyl) oxy-,
  • R 21e ig selected from:
  • C1-C8 alkyl C2-C6 alkenyl, C3-C11 cycloalkyl, (C3- C11 cycloalkyl) ethyl, aryl, aryl (C1-C4 alkyl)-, and
  • R 22e ig selected from:
  • n e is 0-4;
  • p e is 0-2;
  • n e and m e are chosen such that the number of atoms connecting R 1 and -COR 2 0 e in Formula (IV) is in the range of 8-14;
  • d is selected from 1, 2, 3, 4, and 5;
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-1 R 10 , C3-10 cycloalkyl substituted with 0-1 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 1 ⁇ ;
  • k is 0 or 1; s is selected from 0, 1, 2, 3, 4, and 5; s ' is selected from 0, 1, 2, 3, 4, and 5; s" is selected from 0, 1, 2, 3, 4, and 5; t is selected from 0, 1, 2, 3, 4, and 5;
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 1 , NR 13 R 14 , S, SH, S(Pg), OH, and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C3-10 cycloalkyl substituted with 0-3
  • R 17 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 1 ;
  • R 13 , and R 14 are each independently selected from the group: a bond to L n , hydrogen, C1-C10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3
  • R 17 a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
  • R 18 , R 18 , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, and C1-C
  • R 2 ⁇ and R 21 are independently selected from the group:
  • R 23 aryl substituted with 0-3 R 23 , and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 23 ;
  • R 21 - 1 and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group: H, and R 24 ;
  • R 25 is independently selected at each occurrence from the group: H and C1-C3 alkyl.
  • the present invention provides a kit according to Embodiment [1] or [8], wherein:
  • R le is selected from:
  • R 2e and R 3e are independently selected from:
  • R 2ae ig selected from:
  • C3-C7 cycloalkyl (C1-C4 alkyl), aryl, aryl(C ⁇ -C4 alkyl)-, (C2-C7 alkyl) carbonyl, arylcarbonyl,
  • R e is selected from:
  • G e is N or CR 19e ;
  • R 8e is H
  • R 9e is selected from:
  • R 1( ⁇ e is selected from:
  • R ⁇ e is selected from:
  • NR 10e SO2R 21e S(0) p R lle , S02NR 10e R 11 e, aryl substituted with 0-3 groups selected from halogen, C1-C4 alkoxy, C1-C4 alkyl, CF3 ,
  • R lle i s selected from:
  • R 4e is selected from:
  • Ci-C 4 alkyl C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl (C- ⁇ -C ⁇ alkyl)-, aryl, heteroaryl, aryl alkyl)-, and heteroaryl (C 1 -C 4 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3 , and NO2 ,
  • R 12e ig selected from: H, C1-C4 alkyl, (C1-C4 alkyl ) carbonyl , (C1-C4 alkoxy) carbonyl, phenyl (C1-C4 alkyl)-, phenylsulfonyl, phenyloxycarbonyl, and phenyl (C1-C4 alkoxy) carbonyl, wherein said phenyl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3 , and nitro;
  • R 16e ig selected from:
  • R 17e is selected from:
  • C1-C4 alkyl C3-C6 cycloalkyl, C3-C6 cycloalkyl (C1-C4 alkyl)-, aryl, aryl(C ⁇ -C6 alkyl)-, and heteroaryl (C1-C6 alkyl);
  • R 18ae is selected from:
  • C1-C8 alkyl optionally substituted with a bond to Ln
  • C3-C11 cycloalkyl optionally substituted with a bond to L n
  • (Ci-C ⁇ alkyl) heteroaryl optionally substituted with a bond to L n biaryl (C1-C6 alkyl) optionally substituted with a bond to L n
  • heteroaryl optionally substituted with a bond to L n
  • a bond to L n wherein said aryl or heteroaryl groups are optionally
  • R 19e ig selected from:
  • C3-C6 cycloalkyl C3 ⁇ Cg cycloalkyl (C1-C4 alkyl)-, aryl(C ⁇ C4 alkyl)-, Ci-Cg alkoxy, C1-C4 alkoxycarbonyl, aryl, aryl-O-, aryl-S02 ⁇ , heteroaryl, and heteroaryl-S02 ⁇ , wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3 , C1-C3 alkyl, and C1-C3 alkoxy;
  • R 20e ig selected from: hydroxy, Ci-C ⁇ alkyloxy, C3-C6 cycloalkyloxy, aryloxy, aryl (C1-C4 alkyl) oxy, 2- 10 alkylcarbonyloxy(C ⁇ -C2 alkyl) oxy-, 2 _ lO alkoxycarbonyloxy (C1-C2 alkyl) oxy-, C2- 10 alkoxycarbonyl (C1-C2 alkyl) oxy-, C3-C10 cycloalkylcarbonyloxy (C1-C2 alkyl) oxy-, C3-C10 cycloalkoxycarbonyloxy (C1-C2 alkyl) oxy-, C3-C10 cycloalkoxycarbonyloxy (C1-C2 alkyl) oxy-, C3-C10 cycloalkoxycarbonyl (C1-C2 alkyl) oxy-, aryloxycarbony1 (Ci-
  • 21e ig selected from: C1-C4 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, (C3- Cg cycloalkyl) methyl, aryl, aryl(C ⁇ C4 alkyl)-, and
  • n e is 0-4;
  • p e is 0-2;
  • a 1 is selected from the group: OH, and a bond to L n ;
  • a 2 , A 4 , and A 6 are each N;
  • a 3 , A 5 , and A 8 are each OH;
  • a 7 is a bond to L n or NH-bond to L n ;
  • E is a C2 alkyl substituted with 0-1 R 17 ;
  • a 1 is selected from the group: OH, and a bond to L n ;
  • a 2 , A 3 and A 4 are each N;
  • a 5 , A 6 and A 8 are each OH;
  • a 7 is a bond to L n ;
  • E is a C2 alkyl substituted with 0-1 R 17 ;
  • C is ;
  • a 2 is NHR 13 ;
  • R 13 is a heterocycle substituted with R 17 , the heterocycle being selected from pyridine and pyrimidine;
  • R 18 is a bond to L n ;
  • R 24 is selected from the group: -CO2R 25 , -OR 25 , -SO3H, and -N(R 25 )2; and, R 25 is independently selected at each occurrence from the group : hydrogen and methyl .
  • the present invention provides a kit according to Embodiment [1] , wherein: Q is selected from the group:
  • the present invention provides a kit according to Embodiment [1] , wherein the compound is selected from the group:
  • the present invention provides a kit according to Embodiment [1] , wherein the kit further comprises one or more ancillary ligands and a reducing agent.
  • the present invention provides a kit according to Embodiment [12], wherein the ancillary ligands are tricine and TPPTS.
  • the present invention provides a kit according to Embodiment [12], wherein the reducing agent is tin (II).
  • the present invention provides a therapeutic radiopharmaceutical composition
  • a therapeutic radiopharmaceutical composition comprising at least one agent selected from the group consisting of an anti-cancer agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a radiopharmaceutical comprising: a) a metal; b) a chelator capable of chelating the metal; and c) a targeting moiety; wherein the targeting moiety is bound to the chelator through 0-1 linking groups, and the targeting moiety is a quinolone non-peptide that binds to a receptor that is upregulated during angiogenesis.
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [15] , wherein the anti-cancer agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifl
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [15] , wherein radiosensitizer agent is selected from the group consiting of 2- (3- nitro-1, 2 , 4-triazol-l-yl) -N- (2-methoxyethyl) acetamide, N- (3-nitro-4-quinolinyl) -4-morpholinecarboxamidine, 3- amino-1, 2 , 4-benzotriazine-l, 4-dioxide, N-(2- hydroxyethyl) -2-nitroimidazole-l-acetamide, 1- (2- nitroimidazol-1-yl) -3- (1-piperidinyl) -2-propanol, and 1-
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [15] , wherein the metal is selected from the group 33 P, 125 I, 186 Re, 188 Re, 153 Sm, 166 HO; 177 LU/ 149 Pm , 90 Y 212 Bi/ 103 Pd/ 109 Pd 159 Gd/ 14 °La, 1 8 Au, 1 Au, 169 ⁇ b, 1 5 Yb, ⁇ Dy, 166 Dy , 67 Cu , 105 h, lll ⁇ g, a d 192 Ir, and the linking group is present between the non-peptide targeting moiety and chelator.
  • the metal is selected from the group 33 P, 125 I, 186 Re, 188 Re, 153 Sm, 166 HO; 177 LU/ 149 Pm , 90 Y 212 Bi/ 103 Pd/ 109 Pd 159 Gd/ 14 °La, 1 8 Au, 1 Au, 169 ⁇ b, 1 5
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [18] , wherein the targeting moiety is a quinolone non-peptide and the receptor is ⁇ v ⁇ 3 or ⁇ v ⁇ s-
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [15] , wherein the radiopharmaceutical comprises: a) a metal selected from the group 33 P, 125 I, 18 6Re, 188 Re , l 5 3 Sm , 166 Ho , 177 Lu, 14 Pm, 9 °Y, 212 Bi, 103 Pd , 109 Pd , 159 Gd , 140 La , 198 Au , 199 Au , 169 ⁇ b , 175 Yb , 165 Dy , 166 Dy , 67 CU/ 105 Rh , HlAg, and 192 Ir; and b) a compound of the formula (I) :
  • R le is selected from:
  • a e is -CH2- or -N(R 10e )-;
  • a le and B e are independently -CH2- or -N(R 10e )- ;
  • D e is -N(R 10e )- or -S-;
  • K e , L e and M e are independently -C(R 2e )- or -C(R 3e )-;
  • R e and R 3e are independently selected from:
  • R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2 ;
  • R 2ae ig selected from:
  • R 7e is selected from:
  • U e is selected from: - ( CH 2 ) n e -, - ( CH2)n e O ( CH 2 ) m e -, -
  • G e is N or CR 19e ;
  • R ⁇ e is selected from: H, C1-C 0 alkyl, hydroxy, C1-C10 alkoxy, nitro, Ci-
  • NR 10e SO2R 21e S(0) p R lle , S ⁇ 2NR 10e R lle , aryl substituted with 0-3 groups selected from halogen, Ci-C ⁇ alkoxy, C ⁇ Cg alkyl, CF3 ,
  • RiOe i s selected from:
  • R lle is selected from:
  • Ci-Cs alkyl C3 ⁇ Cg alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, Ci-Cg alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl (C ⁇ C4 alkyl)-, aryl (C1-C4 alkyl), adamantylmethyl , and C1-C10 alkyl substituted with 0-2 R e ;
  • R e is selected from:
  • R 12e is selected from:
  • C1-C6 alkyl triphenylmethyl , methoxymethyl , methoxyphenyldiphenylmethyl , trimethylsilylethoxymethyl, (C1-C6 alkyl) carbonyl, ( C ⁇ -CQ alkoxy) carbonyl, (C -C ⁇ alkyl ) aminocarbonyl , C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, heteroaryl (C1-C6 alkyl) carbonyl, heteroarylcarbonyl , aryl (C1-C6 alkyl)-, (Ci-Cg alkyl ) carbonyl , arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl (Ci-C ⁇ alkyl) sulfonyl, heteroarylsulfon
  • R 17e is selected from:
  • Ci-Cg alkyl C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, aryl(C ⁇ -C ⁇ alkyl)-, and heteroaryl (Ci-Cg alkyl);
  • R 18ae i s selected from:
  • R 19e i s selected from:
  • 20e i s selected from: hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, aryloxy, aryl(C ⁇ C4 alkyl) oxy, C2-C10 alkylcarbonyloxy (C1-C2 alkyl) oxy-, 2- 10 alkoxycarbonyloxy (C1-C2 alkyl) oxy-,
  • R 21e is selected from:
  • R 22e i s selected from:
  • Y e is selected from:
  • n e is 0-4 ;
  • p e is 0-2 ;
  • r e is 0 -2 ;
  • n e and m e are chosen such that the number of atoms connecting R le and Y e is in the range of 8-14;
  • d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • d' is 1-100
  • L n is a linking group having the formula:
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-3 RiO, C3.-10 cycloalkyl substituted with 0-3 R 1 ⁇ , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 RiO;
  • R 11 is independently selected at each occurrence from the group: H, -OPO3H2,, -OSO3H C ⁇ _ 5 alkyl substituted with 0-1 R 1 , aryl substituted with 0-1
  • R 12 a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 12 ,
  • R 12 is a bond to Ch
  • k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; h' is selected from 0, 1, and 2; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g' is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and
  • s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s' is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and
  • s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and
  • Ch is a metal bonding unit having a formula selected from the group:
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 S f SH , s(Pg), 0, OH, PR 13 , PR 13 R 14 , P(0)R 15 R 16 , and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C3-10 cycloalkyl substituted with 0-3
  • heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and
  • Ci-io alkyl-C6-io aryl- substituted with 0-3 R 17 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
  • R 13 and R 14 are each independently selected from the group: a bond to L n , hydrogen, Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , Ci-io cycloalkyl substituted with 0-3 R 17 , heterocyclo-Ci-io alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, C6-10 aryl-Ci-io alkyl substituted with 0-3 R 17 , Ci-io alkyl-C6-10 aryl- substituted with 0-3 R 17 , a
  • R 15 and R 1 ⁇ are each independently selected from the group: a bond to L n , -OH, C -Cio alkyl substituted with 0-3 R 17 , Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-Ci-io alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, Cg-10 aryl-Ci-10 alkyl substituted with 0-3 R 17 , Ci-io alkyl-Cg-io aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 ;
  • R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, C1-C6 alkyl, phenyl, benzyl, Ci-Cg alkoxy, halide, nitro, cyano, and trifiuoromethyl;
  • Pg is a thiol protecting group
  • R 2 *- 1 and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group:
  • R 24 C1-C10 alkyl substituted with 0-3 R 24 , C2-C10 alkenyl substituted with 0-3 R 24 , C2-C10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 24 , and C3-10 carbocycle substituted with 0-3 R 24 ;
  • R 25, 25a / an 26 are eac h independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [20] , wherein Q is a compound of Formula (IV) :
  • le is selected from:
  • R 2e and R 3e are independently selected from:
  • R 2ae ig selected from:
  • C3-C7 cycloalkyl (C1-C4 alkyl), aryl, aryl(C ⁇ -C4 alkyl)-, (C2-C7 alkyl) carbonyl, arylcarbonyl,
  • R 7e is selected from:
  • G e is N or CR 19e ;
  • R 8e is selected from:
  • R 9e is selected from:
  • R ⁇ e is selected from: H, Ci-Cio alkyl, hydroxy, Ci-Cio alkoxy, nitro, C ⁇
  • NR 10e SO2R 21e S(0) p e R lle , S ⁇ 2NR 10e R lle , aryl substituted with 0-3 groups selected from halogen, C ⁇ C6 alkoxy, C ⁇ C6 alkyl, CF3 ,
  • R 10e ig selected from: H, -OH, CF3, C3-C6 alkenyl, C3-C11 cycloalkyl, aryl, (C3-C11 cycloalkyl) methyl, aryl(C ⁇ -C4 alkyl), and C1-C10 alkyl substituted with 0-2 R 6e ;
  • R lle is selected from:
  • R 4e is selected from:
  • C- j _-Cg alkyl C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl (C-L-C4 alkyl)-, aryl, heteroaryl, aryl(C 1 -Cg alkyl)-, and heteroaryl (C ⁇ -Cg alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl,
  • R 12e is selected from:
  • C1-C6 alkyl triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl , trimethylsilylethoxymethyl, (C -C6 alkyl) carbonyl , (C1-C6 alkoxy) carbonyl, (C1-C6 alkyl) aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, heteroaryl (C1-C6 alkyl) carbonyl, heteroarylcarbonyl, aryl(C ⁇ -C ⁇ alkyl)-, (Ci-C ⁇ alkyl) carbonyl, arylcarbonyl, Ci-C ⁇ alkylsulfonyl, arylsulfonyl, aryl (C1-C6 alkyl ) sulfonyl , heteroarylsulfonyl , hetero
  • 16e i s selected from:
  • R 17e ig selected from:
  • C1-C6 alkyl C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, aryl(C ⁇ -C6 alkyl)-, and heteroaryl (C1-C alkyl);
  • 18ae is selected from:
  • C1-C8 alkyl optionally substituted with a bond to L n
  • C3-C11 cycloalkyl optionally substituted with a bond to L n
  • (C1-C6 alkyl) heteroaryl optionally substituted with a bond to L n
  • biaryl C1-C6 alkyl) optionally substituted with a bond to L n
  • heteroaryl optionally substituted with a bond to L n
  • R 18be is H or R 18 ae.
  • R 19e ig selected from:
  • R 20e ig selected from: hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, aryloxy, aryl(C ⁇ -C4 alkyl) oxy, 2- 10 alkylcarbonyloxy(C1-C2 alkyl) oxy-, 2- 10 alkoxycarbonyloxy (C1-C2 alkyl) oxy-, 2- ⁇ o alkoxycarbonyl (C1-C2 alkyl) oxy-, C3-C10 cycloalkylcarbonyloxy (C1-C2 alkyl) oxy-, C3-C10 cycloalkoxycarbonyloxy (C1-C2 alkyl) oxy-, C3-C10 cycloalkoxycarbonyloxy (C1-C2 alkyl) oxy-, C3-C10 cycloalkoxycarbonyl (C1-C2 alkyl) oxy-, aryloxycarbonyl (C1-C2
  • R 21e is selected from: C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3- Cll cycloalkyl) methyl, aryl, aryl(C ⁇ -C4 alkyl)-, and Cl-Cio alkyl substituted with 0-2 R 7e ;
  • R.22e i s selected from:
  • n e is 0-4;
  • p e is 0-2;
  • n e and m e are chosen such that the number of atoms connecting R 1 and -C0R 2( - )e in Formula (IV) is in the range of 8-14;
  • d is selected from 1, 2, 3, 4, and 5; d' is 1-50 ;
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-1 RiO, C3-10 cycloalkyl substituted with 0-1 RIO, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 1( ⁇ ;
  • k is 0 or 1; s is selected from 0, 1, 2, 3, 4, and 5; s' is selected from 0, 1, 2, 3, 4, and 5; s" is selected from 0, 1, 2, 3, 4, and 5; t is selected from 0, 1, 2, 3, 4, and 5; A 1 , A 2 , A 3 , A , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), OH, and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C3-10 cycloalkyl substituted with 0-3
  • R 17 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 ;
  • R 13 , and R 14 are each independently selected from the group: a bond to L n , hydrogen, C1-C10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3
  • R 17 a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
  • R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, and C1-C6 alkyl;
  • R 2 ⁇ and R 21 are independently selected from the group: H, C1-C5 alkyl, -CO2R 25 , C2-C5 1-alkene substituted with 0-3 R 23 , C2-C5 1-alkyne substituted with 0-3
  • R 23 aryl substituted with 0-3 R 23 , and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 23 ;
  • R ⁇ and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group: H, and R 24 ; alternatively, R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0;
  • R 25 is independently selected at each occurrence from the group: H and C1-C3 alkyl.
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [20] , wherein: R le is selected from:
  • R 2e and R 3e are independently selected from:
  • R 2e and R e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
  • R 2ae is selected from: H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl), aryl, aryl(C ⁇ -C4 alkyl)-, (C2-C7 alkyl ) carbonyl , arylcarbonyl , (C2-C10 alkoxy) carbonyl, C3-C7 cycloalkoxycarbonyl, C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl (C1-C10 alkoxy) carbonyl,
  • R 7e is selected from:
  • U e is selected from:
  • G e is N or CR 19e ;
  • R 8e is H
  • CONR 18ae R 20e , S02R 18ae , and S ⁇ 2NR 18ae R 20e providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
  • R 10e is selected from:
  • R ⁇ e is selected from:
  • R lle ig selected from: H, hydroxy, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) methyl, C1-C4 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl (C1-C4 alkyl)-, aryl (C1-C4 alkyl), adamantylmethyl , and C1-C4 alkyl substituted with 0-2 R e ;
  • R 4e is selected from:
  • Ri ⁇ e is selected from:
  • R 17e is selected from: H, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl (C1-C4 alkyl)-, aryl, aryl(C ⁇ C6 alkyl)-, and heteroaryl (C1-C6 alkyl);
  • R 18ae is selected from: C1-C8 alkyl optionally substituted with a bond to Ln, C3-C11 cycloalkyl optionally substituted with a bond to L n , aryl (C1-C6 alkyl) - optionally substituted with a bond to L n , heteroaryl (C1-C6 alkyl)- optionally substituted with a bond to L n , (Ci-C ⁇ alkyl) heteroaryl optionally substituted with a bond to L n , biaryl (C1-C6 alkyl) optionally substituted with a bond to Ln, heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroary
  • R 19e ig selected from: H, halogen/ CF3 , CO2H, CN, NO2 , -NR lle R 12e , OCF3 , Ci-C ⁇ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl (C1-C4 alkyl)-, aryl(C ⁇ -C4 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl, aryl, aryl-0-, aryl-S02-, heteroaryl, and heteroaryl-S02- , wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3 , C1-C3 alkyl, and C1-C3 alkoxy;
  • R.20e is selected from: hydroxy, C1-C6 alkyloxy, C3-C6 cycloalkyloxy, aryloxy, aryl (C1-C4 alkyl) oxy, C2-C10 alkylcarbonyloxy (C1-C2 alkyl) oxy-, C2- 10 alkoxycarbonyloxy (C1-C2 alkyl) oxy-, C2-C10 alkoxycarbonyl (C1-C2 alkyl) oxy-, C3-C10 cycloalkylcarbonyloxy (C1-C2 alkyl) oxy-, C3-C10 cycloalkoxycarbonyloxy (C1-C2 alkyl) oxy-, C3-C10 cycloalkoxycarbonyloxy (C1-C2 alkyl) oxy-, C3-C10 cycloalkoxycarbonyl (C1-C2 alkyl) oxy-, aryloxycarbonyl (C1-
  • R 21e is selected from:
  • C1-C4 alkyl C2-C6 alkenyl, C3-C6 cycloalkyl, (C3- C ⁇ cycloalkyl) ethyl, aryl, aryl(C ⁇ -C4 alkyl)-, and
  • R22 ⁇ ig selected from:
  • n e is 0-4;
  • a 1 is selected from the group: OH, and a bond to L n ;
  • a 2 , A 4 , and A 6 are each N;
  • a 3 , A 5 , and A 8 are each OH;
  • a 7 is a bond to L n or NH-bond to L n ;
  • E is a C2 alkyl substituted with 0-1 R 17 ;
  • Ch is
  • a 1 is selected from the group: OH, and a bond to L n ;
  • a 2 , A 3 and A 4 are each N;
  • a 5 , A 6 and A 8 are each OH;
  • a 7 is a bond to L n ;
  • E is a C2 alkyl substituted with 0-1 R 17 ;
  • Ch is A ;
  • a 2 is NHR 13 ;
  • R 13 is a heterocycle substituted with R 17 , the heterocycle being selected from pyridine and pyrimidine;
  • R 18 is a bond to L n ;
  • R 24 is selected from the group: -CO2R 25 , -OR 25 , -SO3H, and -N(R 25 )2; and, R 25 is independently selected at each occurrence from the group : hydrogen and methyl .
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [20] , wherein Q is selected from the group :
  • the present invention provides a composition according to Embodiment [18] , wherein the radioisotope is 1 7 Lu.
  • the present invention provides a composition according to Embodiment [25] , wherein the radiopharmaceutical is selected from the group :
  • the present invention provides a composition according to Embodiment [18] , wherein the radioisotope is 0 ⁇ .
  • the present invention provides a composition according to Embodiment [27] , wherein the radiopharmaceutical is selected from the group;
  • the present invention provides a method of treating cancer in a patient comprising: administering to a patient in need thereof a therapeutic radiopharmaceutical comprising: a) a metal; b) a chelator capable of chelating the metal; and c) a targeting moiety; wherein the targeting moiety is bound to the chelator through a linking group, and the targeting moiety is a quinolone non-peptide that binds to a receptor that is upregulated during angiogenesis, and the metal is a radioisotope selected from the group: 33 P, 125 I, 1 6Re, 188 Re , 153 sm, i ⁇ ⁇ ⁇ o, 17 Lu, 14 Pm, 9 °Y, 21 Bi, i0 3 d, 109 Pd , 159 Gd , 140 La 198 Au , 199 Au , 169 ⁇ b , 175 Yb/ 165 Dy , 166 Dy , 67 CU/ 105 Rh ,
  • the present invention provides a method according to Embodiment [29] wherein administering the therapeutic radiopharmaceutical and agent is concurrent.
  • the present invention provides a method according to Embodiment [29] wherein administering the therapeutic radiopharmaceutical and agent is sequential.
  • the present invention provides a method according to Embodiment [29] wherein the cancer is selected from the group consisting of carcinomas of the lung, breast, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, and neuroblasto as .
  • the cancer is selected from the group consisting of carcinomas of the lung, breast, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas
  • the present invention provides a method according to Embodiment [29] wherein the anti-cancer agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate
  • the present invention provides a method according to Embodiment [29] wherein the radiosensitizer agent is selected from the group consisting of 2- (3-nitro-l, 2 , 4-triazol-l-yl) -N- (2- methoxyethyl) acetamide, N- (3-nitro-4-quinolinyl) -4- morpholinecarboxamidine, 3-amino-l, 2 , 4-benzotriazine- 1, 4-dioxide, N- (2-hydroxyethyl) -2-nitroimidazole-l- acetamide, 1- (2-nitroimidazol-l-yl) -3- (1-piperidinyl) - 2-propanol, and 1- (2-nitro-l-imidazolyl) -3- (1- aziridino) -2-propanol.
  • the radiosensitizer agent is selected from the group consisting of 2- (3-nitro-l, 2 , 4-triazol-l-yl) -
  • the present invention provides a method according to Embodiment [29] wherein the anti-cancer agent is a chemotherapeutic agent.
  • the present invention provides a method of treating cancer according to Embodiment [29], wherein the administration is by injection or infusion.
  • the present invention provides a method according to Embodiment [29] , wherein the therapeutic radiopharmaceutical comprises : a) a metal; b) a chelator capable of chelating the metal; and c) a targeting moiety; wherein the targeting moiety is bound to the chelator through a linking group, and the targeting moiety is a quinolone non-peptide that binds to a receptor that is upregulated during angiogenesis, and the metal is a radioisotope selected from the group: 3 P, 125 I, 1 ⁇ Re, 188 Re , 153 Sm/ 166 Ho , 177 Lu , 149 Pm , 90 Y 212 Bi# 103 Pd/
  • the present invention provides a method according to Embodiment [37] , wherein the targeting moiety is a quinolone non-peptide and the receptor is ⁇ v ⁇ 3 or v ⁇ s •
  • the present invention provides a method according to Embodiment [37] , wherein the therapeutic radiopharmaceutical comprises : a) a radioisotope selected from the group: P, 1 I, 18 6 R e, 188 Re, 153 Sm, 166 Ho , 177 LU, 14 Pm, 9 0 Y , 212 B i, 103 Pd 109 Pd , 159 Gd , 140 La , 198 Au , 199 AU/ 169 ⁇ b , 175 Yb 165 D ⁇ , 166 D ⁇ , 67 Cu , 105 Rh/ lll Ag , an d 192 Ir ; and b) a compound of the formula (I) :
  • R le is selected from:
  • a e is -CH2- or -N(R 10e )-;
  • a le and B e are independently -CH2- or -N(R 10e )- ;
  • D e is -N(R 10e )- or -S-;
  • E e_ F e ig -c(R 2e ) C(R 3e )- or -C (R 2e ) 2C (R 3e ) 2 ⁇ ; J e is -C (R 2 e ) - or -N- ;
  • L e and M e are independently -C(R 2e )- or -C(R 3e )-;
  • R 2e and R 3e are independently selected from:
  • R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
  • R 2ae is selected from:
  • R 7e is selected from:
  • U e is selected from: -(CH 2 ) n e -, -(CH2)n e O(CH 2 ) ⁇ e -, -
  • G e is N or CR 19e ;
  • R6 ⁇ is selected from: H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C ⁇
  • NR 10e SO2R 21e S(0) p R lle , S ⁇ 2NR 10e R lle , aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3 ,
  • RiOe is selected from:
  • R lle is selected from:
  • R 4e is selected from:
  • R 12e ig selected from:
  • C1-C6 alkyl triphenylmethyl , methoxymethyl , methoxyphenyldiphenylmethyl , trimethylsilylethoxymethyl, (C1-C6 alkyl ) carbonyl , (C1-C6 alkoxy) carbonyl, (C1-C6 alkyl) minocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, heteroaryl (C1-C6 alkyl ) carbonyl , heteroarylcarbonyl , aryl(C ⁇ -Cg alkyl)-, (C1-C6 alkyl) carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl (C1-C6 alkyl) sulfonyl, heteroarylsulfon
  • R 17e is selected from:
  • C1-C8 alkyl optionally substituted with a bond to L n C3-C11 cycloalkyl optionally substituted with a bond to L n , aryl(C ⁇ -C6 alkyl) - optionally substituted with a bond to L n , heteroaryl (Ci-C ⁇ alkyl)- optionally substituted with a bond to L n , (C1-C6 alkyl) heteroaryl optionally substituted with a bond to L n , biaryl (C1-C6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substitute
  • R 19 e is " selected from:
  • R 20e ig selected from: hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, aryloxy, aryl(C ⁇ -C4 alkyl) oxy, C2-C10 alkylcarbonyloxy(C ⁇ -C2 alkyl) oxy-, 2- 10 alkoxycarbonyloxy(C ⁇ -C2 alkyl) oxy-, 2- 10 alkoxycarbonyl (C1-C2 alkyl) oxy-,
  • R 21e is selected from:
  • C1-C8 alkyl C2-C6 alkenyl, C3-C11 cycloalkyl, (C3- Cll cycloalkyl) methyl, aryl, aryl(C ⁇ -C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R 7e ;
  • R 22e ig selected from:
  • Y e is selected from:
  • n e is 0-4;
  • p e is 0-2;
  • r e is 0-2;
  • n e and m e are chosen such that the number of atoms connecting R le and Y e is in the range of 8-14; 0 d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • d' is 1-100
  • 5 n is a linking group having the formula:
  • 5 aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-3 R 10 , C3-10 cycloalkyl substituted with 0-3 R!0, and a 5-10 membered heterocyclic ring system containing 0 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R10;
  • R 11 is independently selected at each occurrence from the group: H, -OPO3H2,, -OSO3H C ⁇ _5 alkyl substituted with 0-1 R 12 , aryl substituted with 0-1
  • R 12 a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 12 ,
  • R 12 is a bond to Ch
  • Ch is a metal bonding unit having a formula selected from the group :
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14, s , SH/ s(Pg), 0, OH, PR 13 , PR 13 R 14 , P(0)R 15 R 16 , and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Ci-C o alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C3-10 cycloalkyl substituted with 0-3
  • heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and
  • R 13 and R 14 are each independently selected from the group: a bond to L n , hydrogen, Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , Ci-io cycloalkyl substituted with 0-3 R 17 , heterocyclo-C ⁇ _ ⁇ o alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C ⁇ -io aryl-Ci-io alkyl substituted with 0-3 R 17 , Ci-io alkyl-C6-10 aryl- substituted with 0-3 R 17 ,
  • R 15 and R 1 ⁇ are each independently selected from the group: a bond to L n , -OH, Ci-Cio alkyl substituted with 0-3 R 17 , Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-Ci-io alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, C6- 0 aryl-Ci-io alkyl substituted with 0-3 R 17 , C -io alkyl-C6-10 aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 ;
  • R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, C1-C6 alkyl, phenyl, benzyl, C1-C6 alkoxy, halide, nitro, cyano, and trifiuoromethyl;
  • Pg is a thiol protecting group
  • R 21 -* and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group:
  • R 24 Ci-Cio alkyl substituted with 0-3 R 24 , C2-C10 alkenyl substituted with 0-3 R 24 , C2-C10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 24 , and C3_ ⁇ o carbocycle substituted with 0-3 R 24 ;
  • R 25 , R 5a , and R 2 ⁇ are each independently selected at each occurrence from the group: hydrogen and Ci-Cg alkyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method according to Embodiment [39] , wherein: Q is a compound of Formula (IV) :
  • R le is selected from:
  • R 2e and R 3e are independently selected from:
  • R e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
  • R 2ae is selected from: H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl), aryl, aryl(C ⁇ -C4 alkyl)-, (C2-C7 alkyl) carbonyl, arylcarbonyl , (C2-C10 alkoxy) carbonyl, C3-C7 cycloalkoxycarbonyl, C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C ⁇ -C ⁇ o alkoxy) carbonyl,
  • R e is selected from:
  • U e is selected from:
  • R 9e is selected from:
  • R ⁇ e is selected from:
  • Ci-Cio alkyl H, Ci-Cio alkyl, hydroxy, Ci-Cio alkoxy, nitro, C ⁇
  • Cio aIkylcarbonyl , -N(R lle ) R 12e , cyano, halo, CF3, CHO, C02R 18be , C( 0)R 18be , CONR 17e R 18be ,
  • NR 10e SO2R 21e S(0) p e R lle , SO2NR 10e R lle , aryl substituted with 0-3 groups selected from halogen, C ⁇ C6 alkoxy, Ci-C ⁇ alkyl, CF3 ,
  • R 10e is selected from:
  • R lle is selected from:
  • R 4e is selected from: H, C 1 -Cg alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl (C -C4 alkyl)-, aryl, heteroaryl, aryl(C- ] _-Cg alkyl)-, and heteroaryl (C ⁇ -Cg alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3 , and NO2 ,
  • R 12e ig selected from:
  • C1-C6 alkyl triphenylmethyl, methoxymethyl , methoxyphenyldiphenylmethyl , trimethylsilylethoxymethyl, (Ci-C ⁇ alkyl ) carbonyl , (C1-C6 alkoxy) carbonyl, (C1-C6 alkyl) aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, heteroaryl (C1-C6 alkyl ) carbonyl , heteroarylcarbonyl , aryl (C1-C6 alkyl)-, (C1-C alkyl) carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl(C ⁇ -C6 alkyl) sulfonyl, heteroarylsulfonyl,
  • Ri6 e is selected from:
  • 17e ig selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, aryl, aryl (C1-C6 alkyl)-, and heteroaryl (Ci-C ⁇ alkyl);
  • R 18ae is selected from: C1-C8 alkyl optionally substituted with a bond to Ln, C3-C11 cycloalkyl optionally substituted with a bond to L n , aryl (C1-C6 alkyl) - optionally substituted with a bond to L n , heteroaryl (Ci-C ⁇ alkyl)- optionally substituted with a bond to L n , (Ci-C ⁇ alkyl) heteroaryl optionally substituted with a bond to L n , biaryl (Ci-C ⁇ alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or
  • 19e is selected from:
  • 20e is selected from: hydroxy, C -C10 alkyloxy, C3-C11 cycloalkyloxy, aryloxy, aryl(C ⁇ C4 alkyl) oxy, C2-C10 alkylcarbonyloxy (C1-C2 alkyl) oxy-, c 2- l ⁇ alkoxycarbonyloxy (C1-C2 alkyl) oxy-, 2- l ⁇ alkoxycarbonyl (C1-C2 alkyl) oxy-, 3-C10 cycloalkylcarbonyloxy (C1-C2 alkyl) oxy-,
  • 21e ig selected from:
  • C1-C8 alkyl C2-C6 alkenyl, C3-C11 cycloalkyl, (C3- Cll cycloalkyl) methyl, aryl, aryl(C ⁇ -C4 alkyl)-, and
  • n e is 0-4;
  • p e is 0-2;
  • n e and m e are chosen such that the number of atoms connecting R 1 and -COR 2 ⁇ e in Formula (IV) is in the range of 8-14;
  • d is selected from 1, 2, 3, 4, and 5;
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-1 R!0, C3-10 cycloalkyl substituted with 0-1 R 1 ⁇ , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 1 ⁇ ;
  • k is 0 or 1; s is selected from 0, 1, 2, 3, 4, and 5; s ' is selected from 0, 1, 2, 3, 4, and 5; s" is selected from 0, 1, 2, 3, 4, and 5; t is selected from 0, 1, 2, 3, 4, and 5;
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 1 , NR 13 R 14 , S, SH, S(Pg), OH, and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Cl-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C3-10 cycloalkyl substituted with 0-3
  • R 17 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 ;
  • R 13 , and R 14 are each independently selected from the group: a bond to L n , hydrogen, C1-C 0 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3
  • R 17 a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
  • R 18, R 18a, an R 19 are independently selected at each occurrence from the group: a bond to L n , H, and C1-C
  • R 2 ⁇ and R 21 are independently selected from the group:
  • R 23 aryl substituted with 0-3 R 23 , and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 23 ;
  • R 2 ⁇ and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group: H, and R 24 ;
  • R 25 is independently selected at each occurrence from the group: H and C1-C3 alkyl.
  • the present invention provides a method according to Embodiment [39] , wherein:
  • R le is selected from:
  • R 2e and R 3e are independently selected from:
  • R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and
  • R 7e is selected from:

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Abstract

Cette invention se rapporte à de nouveaux kits et compositions comprenant des composés représentés par la formule (Q)d-Ln-Ch (I), utiles dans le diagnostic et le traitement du cancer chez des patients suivant une polythérapie. Cette invention propose de nouveaux composés utiles dans le traitement de l'arthrite rhumatoïde. Les agents pharmaceutiques faisant l'objet de cette invention sont constitués par une fraction de ciblage qui se fixe à un récepteur régulé en quantité croissante pendant l'angiogenèse, par un groupe de liaison optionnel et par un radio-isotope efficace à des fins thérapeutiques ou par une fraction visible en imagerie efficace à des fins diagnostiques.
PCT/US2001/019793 2000-06-21 2001-06-21 Agents pharmaceutiques antagonistes du recepteur de vitronectine, a utiliser en polytherapie WO2001097848A2 (fr)

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AU7296501A AU7296501A (en) 2000-06-21 2001-06-21 Vitronectin receptor antagonist pharmaceuticals for use in combination therapy
CA2412854A CA2412854C (fr) 2000-06-21 2001-06-21 Agents pharmaceutiques antagonistes du recepteur de vitronectine, a utiliser en polytherapie
NZ522925A NZ522925A (en) 2000-06-21 2001-06-21 Vitronectin receptor antagonist pharmaceuticals for use in combination therapy
IL15294101A IL152941A0 (en) 2000-06-21 2001-06-21 Fused heterocyclic compounds and kits and pharmaceutical compositions containing the same
EP01952180A EP1307226B1 (fr) 2000-06-21 2001-06-21 Agents pharmaceutiques antagonistes du recepteur de vitronectine
JP2002503332A JP2004521066A (ja) 2000-06-21 2001-06-21 併用療法用ビトロネクチン受容体アンタゴニスト医薬
BRPI0111880-3A BR0111880A (pt) 2000-06-21 2001-06-21 produtos farmacêuticos agonistas de receptor de vitronectina para uso em terapia de combinação
AU2001272965A AU2001272965C1 (en) 2000-06-21 2001-06-21 Vitronectin receptor antagonist pharmaceuticals
DE60136632T DE60136632D1 (de) 2000-06-21 2001-06-21 Vitronectin rezeptor antagonist pharmaka
MXPA02012750A MXPA02012750A (es) 2000-06-21 2001-06-21 Compuestos farmaceuticos antagonistas del receptor de la vitronectina para su uso en terapia de combinacion.

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WO2001085212A2 (fr) * 2000-05-08 2001-11-15 The University Of British Columbia Systemes d'apport de medicament, destines a une therapie photodynamique
WO2001097861A2 (fr) * 2000-06-21 2001-12-27 Bristol-Myers Squibb Pharma Company Agents pharmaceutiques antagonistes du recepteur de la vitronectine destines a etre utilises dans une therapie combinee
US6569402B1 (en) 1998-12-18 2003-05-27 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
WO2004098651A3 (fr) * 2003-05-09 2005-04-07 Schering Ag Radiotherapie combinatoire de composes interagissant avec la tubuline et de composes radiopharmaceutiques de localisation osseuse
JP2007505155A (ja) * 2003-05-12 2007-03-08 ブリストル−マイヤーズ・スクイブ・ファーマ・カンパニー ビトロネクチンレセプタ・アンタゴニスト化合物および放射性薬品製造におけるその使用
US7255875B2 (en) 2002-01-24 2007-08-14 Barnes-Jewish Hospital Integrin targeted imaging agents
US10137209B2 (en) 2015-06-04 2018-11-27 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US11814369B2 (en) 2016-11-28 2023-11-14 Bayer Pharma Aktiengesellschaft High relaxivity gadolinium chelate compounds for use in magnetic resonance imaging
US11944690B2 (en) 2018-11-23 2024-04-02 Bayer Aktiengesellschaft Formulation of contrast media and process of preparation thereof

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Cited By (20)

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Publication number Priority date Publication date Assignee Title
US6569402B1 (en) 1998-12-18 2003-05-27 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US7090828B2 (en) 1998-12-18 2006-08-15 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
WO2001085212A2 (fr) * 2000-05-08 2001-11-15 The University Of British Columbia Systemes d'apport de medicament, destines a une therapie photodynamique
WO2001085212A3 (fr) * 2000-05-08 2002-08-08 Univ British Columbia Systemes d'apport de medicament, destines a une therapie photodynamique
US6693093B2 (en) 2000-05-08 2004-02-17 The University Of British Columbia (Ubc) Drug delivery systems for photodynamic therapy
US8968715B2 (en) 2000-05-08 2015-03-03 The University Of British Columbia Drug delivery systems for photodynamic therapy
WO2001097861A2 (fr) * 2000-06-21 2001-12-27 Bristol-Myers Squibb Pharma Company Agents pharmaceutiques antagonistes du recepteur de la vitronectine destines a etre utilises dans une therapie combinee
WO2001097861A3 (fr) * 2000-06-21 2003-02-27 Bristol Myers Squibb Pharma Co Agents pharmaceutiques antagonistes du recepteur de la vitronectine destines a etre utilises dans une therapie combinee
US7344698B2 (en) 2002-01-24 2008-03-18 Barnes-Jewish Hospital Integrin targeted imaging agents
US7255875B2 (en) 2002-01-24 2007-08-14 Barnes-Jewish Hospital Integrin targeted imaging agents
AU2003209392B2 (en) * 2002-01-24 2008-10-09 Barnes Jewish Hospital Integrin targeted imaging agents
US7566442B2 (en) 2002-01-24 2009-07-28 Barnes-Jewish Hospital Integrin targeted imaging agents
EP2269659A1 (fr) 2002-01-24 2011-01-05 Barnes Jewish Hospital Agents de contraste ciblant une intégrine
WO2004098651A3 (fr) * 2003-05-09 2005-04-07 Schering Ag Radiotherapie combinatoire de composes interagissant avec la tubuline et de composes radiopharmaceutiques de localisation osseuse
JP2007505155A (ja) * 2003-05-12 2007-03-08 ブリストル−マイヤーズ・スクイブ・ファーマ・カンパニー ビトロネクチンレセプタ・アンタゴニスト化合物および放射性薬品製造におけるその使用
US10137209B2 (en) 2015-06-04 2018-11-27 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US10722601B2 (en) 2015-06-04 2020-07-28 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US11491245B2 (en) 2015-06-04 2022-11-08 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US11814369B2 (en) 2016-11-28 2023-11-14 Bayer Pharma Aktiengesellschaft High relaxivity gadolinium chelate compounds for use in magnetic resonance imaging
US11944690B2 (en) 2018-11-23 2024-04-02 Bayer Aktiengesellschaft Formulation of contrast media and process of preparation thereof

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EP1307226B1 (fr) 2008-11-19
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CA2412854C (fr) 2010-08-17
ATE414541T1 (de) 2008-12-15
BR0111880A (pt) 2006-04-25
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AU2001272965C1 (en) 2006-06-29
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CA2412854A1 (fr) 2001-12-27
AU2001272965B2 (en) 2005-11-17

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